It is known that methacycline and doxycycline are very effective representatives of tetracycline type antibiotics.
Several processes are known for the preparation thereof using oxytetracycline as starting material and preparing chloromethacycline followed by dehalogenation and if desired by hydrogenation the obtained methacycline to doxycycline.
Dehalogenation was accomplished--among other methods--by introducing hydrogen gas in the presence of a catalyst, see e.g. Example 9 of Hungarian Patent No. 150909, wherein rhodium precipitated on active carbon was used.
This process, however, was not satisfactory as reaction products were produced which were difficult to separate from by-products and the conversion was not complete either. Therefore the use of secondary or tertiary phosphines has been recommended in Hungarian Patent No. 169 605. This process was accompanied with the disadvantage that an equimolar amount of tertiary or secondary phosphines was needed, resulting in a great amount of poisonous waste, and the formed phosphine oxide could be converted again to phosphine only by a multi-step reaction.
The introduction of hydrogen gas in the presence of a catalyst was also used for the saturation of the double bond of the methylene group at the 6-position on methacycline in order to produce doxycycline.
In the course of hydrogenation 6-desoxy-5-hydroxy-tetracycline of the formula (IV) can occur in the form of .alpha.- and .beta.-isomers. Only the .alpha.-isomer is valuable as medicine, i.e. doxycycline. The amount of the .alpha.-isomers during hydrogenation determines if the hydrogenation process is successful, i.e. if hydrogenation can be carried out selectively, to produce mainly .alpha.-isomer with a good yield and pure quality.
It is also known that 6-desoxy-5-hydroxy-tetracycline can be prepared with a yield of 60% by using a 5% palladium or rhodium catalyst on a carrier, but the product was a 1:1 mixture of .alpha.- and .beta.-isomers, which was followed by the separation of the .alpha.-isomer accompanied by further losses (U.S. Pat. No. 3,200,149). The ratio of the formation of the .alpha.-isomer can considerably be improved, if the noble metal catalyst on a carrier is poisoned by carbon monoxide, quinoline sulphur or other sulphur compounds. Thus the yield of the .alpha.-isomer could be increased to 40-50%, but even so the product had to be further purified due to the remaining 10% .beta.-isomer impurities (Hungarian Patent No. 156 925). In order to improve the stereoselectivity of hydrogenation an alloy catalyst consisting of the metals of platinum group, copper, silver or gold has been used and a doxycycline yield of about 70% has been disclosed with 1 to 10% .beta.-isomer impurities (Hungarian Patent No. 167 250).
A 92% .alpha.-isomer content has been achieved by using a catalyst containing palladium atoms located on ultra-microporous active carbon, without poisoning, with a yield of 76% (Hungarian Patent No. 169 667).
Hydrogenation could be performed by using Raney nickel and Raney cobalt as a catalyst according to GB-PS No. 1 296 340, but the formation of .alpha.-isomer in the reaction mixtures amounted only to about 40%. According to Finnish Patent No. 67210 to palladium/charcoal catalyst a complex of bis(diphenylselenide) palladium(II)chloride was added resulting thus in a yield of 75%, wherein the ratio of the .alpha.-isomer was about 95%. According to the disclosure this effect could not be achieved if diphenylselenide was not used in a complex form.
In order to give a complete review of the known processes, we mention those hydrogenation processes, which are not close to our process, but wherein hydrogenation was performed by using triphenyl phosphine rhodium complexes, being catalysts which are soluble in the reaction mixture (DE-OS No. 2 403 714) or by using further additives next to the complexes (Hungarian Patent Nos. 169 753, 169 508, 173 508 and 187 465).
Doxycycline could thus be prepared with a good yield and selectivity.
Inspite of the significant development the known processes show many drawbacks. As already mentioned the use of the known heterogeneous catalysts only partially solves the problem of stereoselectivity. A considerable amount of these catalysts had to be used, and so the ratio substrate-catalyst was not favorable. The relative great amount of the used solvent was also unfavorable. Although the catalysts can be removed from the reaction mixture by filtration, the solvent has to be recovered before use by a costly and inefficient procedure.
In the case of homogenous catalysis the catalyst is in solution and its isolation is not easy. Rhodium is very expensive, it is difficult to obtain, its recovery is complicated, expensive and it can contaminate the product.
According to the present invention methacycline and doxycycline are prepared in a heterogeneous layer, wherein dehalogenation can be performed with good yield and reduction takes place stereoselectivetly and the side reactions can be eliminated to such extent that no extra purification of the product is needed and the used catalyst can be prepared simply and the specific costs of the catalyst are low. Dehalogenation and hydrogenation can be effected without any extra equipment by using the same type of catalyst. Thus the needed medicine can be prepared.